A Peptide against Soluble Guanylyl Cyclase α1: A New Approach to Treating Prostate Cancer

Among the many identified androgen-regulated genes, sGC alpha 1 (soluble guanylyl cyclase alpha 1) appears to play a pivotal role in mediating the pro-cancer effects of androgens and androgen receptor. The classical role for sGC alpha 1 is to heterodimerize with the sGC beta 1 subunit, forming sGC, the enzyme that mediates nitric oxide signaling by catalyzing the synthesis of cyclic guanosine monophosphate. Our published data show that sGC alpha 1 can drive prostate cancer cell proliferation independent of hormone and provide cancer cells a pro-survival function, via a novel mechanism for p53 inhibition, both of which are independent of sGC beta 1, NO, and cGMP. All of these properties make sGC alpha 1 an important novel target for prostate cancer therapy. Thus, peptides were designed targeting sGC alpha 1 with the aim of disrupting this protein's pro-cancer activities. One peptide (A-8R) was determined to be strongly cytotoxic to prostate cancer cells, rapidly inducing apoptosis. Cytotoxicity was observed in both hormone-dependent and, significantly, hormone-refractory prostate cancer cells, opening the possibility that this peptide can be used to treat the usually lethal castration-resistant prostate cancer. In mouse xenograft studies, Peptide A-8R was able to stop tumor growth of not only hormone-dependent cells, but most importantly from hormone-independent cells. In addition, the mechanism of Peptide A cytotoxicity is generation of reactive oxygen species, which recently have been recognized as a major mode of action of important cancer drugs. Thus, this paper provides strong evidence that targeting an important AR-regulated gene is a new paradigm for effective prostate cancer therapy.